Method for prevention of colectomy

ABSTRACT

A method of treating chronic active ulcerative colitis in a subject that is refractory or responds insufficiently or is intolerant to anti-inflammatory therapy, comprises administering to a patient in need thereof an effective exposure of an oligonucleotide comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO.2), wherein at least one CG dinucleotide is unmethylated. The oligonucleotide is not administered with corticosteroids or glucocorticosteroids.

The present application incorporates by reference the Sequence Listingfiled herewith entitled “Sept-14-2016-Sequence-Listing-205087A.txt”created Sep. 13, 2016 and having a size of 1131 bytes.

FIELD OF THE INVENTION

The present invention relates to methods of preventing or reducing theneed of colectomy. In particular, the present invention relates to anoligonucleotide, for use in the treatment of an inflammatory boweldisease, such as ulcerative colitis (UC) or Crohn's disease, in asubject that is refractory or responds insufficiently or is intolerantto anti-inflammatory therapy, wherein said oligonucleotide isrepetitively administered as a single exposure. Further, the presentinvention relates to pharmaceutical compositions comprising saidoligonucleotide for the prevention or reduction of need of colectomy.

BACKGROUND OF THE INVENTION

Colectomy is the surgical resection of any extent of the large intestineand is often the clinical endpoint intervention for medical indicationssuch as colon cancer and inflammatory bowel disease (IBD), for exampleUC.

While the understanding of the etiology of UC has grown over the years,the picture emerging is one of a complex interplay between genetic (Choand Brant, 2011; Thompson and Lees, 2011), microbial (Wine et al., 2010)and environmental factors (Cosnes, 2010) as well as intestinalepithelial function (Schmitz et al., 1999) and mucosal immune system(Heller et al., 2002). No factor alone appears to be sufficient totrigger the development of the disease and the contribution of eachindividual component may vary between patients (Xavier and Podolsky,2007). Clinical presentation of UC depends upon the extent and severityof the disease however predominate features includes blood in stool,stool frequency, passage of mucopus and possible abdominal pain (Riegleret al., 2000).

Effective clinical management of active UC requires a comprehensiveunderstanding of the disease extent, the severity and the potentialrisks and benefits of the available interventions with focus on theinduction and maintenance of remission. Corticosteroids remain thecornerstone of initial therapy yet a third of patients will fail torespond, and further management involves critical and timely decisionson whether to use rescue therapy in the form of immunomodulatory drugssuch as Ciclosporine A or anti-TNF therapies such as Infliximab (Turneret al., 2007). Current data suggest that rescue with Ciclosprine A andInfliximab are efficacious in the short to medium term perspective(Wilhelm et al., 2008; Filippi et al., 2011) but the long term outcomeseems less efficacious (Sjöberg et al., 2011). Furthermore, asignificant proportion of UC patients will have recurrent flares orchronic continuous disease despite receiving conventional symptomatictreatment and within a 10 year period, some 20 percent of these patientswill require surgical intervention (Langholz et al., 1994).

While surgical intervention may be curative and provide a better qualityof life (Weinryb et al., 1995), it is not without considerable risks tothe patient (Ferrante et al., 2008) and the procedure itself presents asignificant pre- and postoperative morbidity as well as an economicburden to the healthcare system (Rubin et al., 2009). Consequently,there is an urgent need for alternative treatments.

SUMMARY OF THE INVENTION

The present invention relates to methods of preventing or reducing theneed of colectomy. In particular, the present invention relates amethod, wherein an effective amount of an oligonucleotide comprising thesequence 5′-X_(m)-TTCGT-Y_(n)-3′ is administered repetitively as asingle exposure to a subject in need thereof, for the prevention ofcolectomy, wherein X is A, T, C or G, Y is A, T, C or G, m=0-12, n=0-12and wherein at least one CG dinucleotide is unmethylated. Further thepresent invention relates to pharmaceutical compositions comprising saidoligonucleotide together with one or more pharmaceutically acceptableexcipient(s) and/or carrier(s), as well as exposure regimes of saidoligonucleotide for preventing or reducing the need of colectomy. Inparticular, the present invention relates to methods of preventing orreducing the need of colectomy. In particular, the present inventionrelates to an oligonucleotide, for use in the treatment of aninflammatory bowel disease, such as ulcerative colitis (UC) or Crohn'sdisease, in a subject that is refractory or responds insufficiently oris intolerant to anti-inflammatory therapy, wherein said oligonucleotideis repetitively administered as a single exposure.

BRIEF DESCRIPTION OF THE FIGURES

These and other aspects of the invention will now be described infurther detail, with reference to the appended figures.

FIG. 1 represents a graph showing the median change in CAI score (boldvalues) following single exposure (continuous line) or multipleexposures (hatched line) of DIMS0150 (SEQ ID NO:1) therapy. Verticalbars give the range values.

FIG. 2 represents a graph showing median change in endoscopic scoreaccording to Rachmilewitz et. al, (bold values) following singleexposure (continuous line) or multiple exposures (hatched line) ofDIMS0150 (SEQ ID NO:1) therapy. Vertical bars give the range values.

FIG. 3 represents a graph showing median change in histological scoreaccording to Geboes et. al, (bold values) following single exposure(continuous line) or multiple exposures (hatched line) of DIMS0150 (SEQID NO:1) therapy. Vertical bars give the range values.

FIG. 4 represents a graph showing the length of colectomy-free periodfollowing DIMS0150 (SEQ ID NO:1) therapy. Black bars representcolectomized patients. Data compiled from August 2008 to March 2011.

DETAILED DESCRIPTION

All patents, patent applications, and publications cited herein arehereby incorporated by reference in their entirety.

As used herein, the term inflammatory bowel disease (IBD) refers to agroup of inflammatory conditions of the colon and the small intestine.The major types of IBD are UC and Crohn's disease. The main differencebetween UC and Crohn's disease is the location and nature of theinflammatory changes. Crohn's disease can affect any part of thegastrointestinal tract, from mouth to anus, while UC is most oftenrestricted to the colon and the rectum. In rare cases, a definitivediagnosis of either Crohn's disease or UC cannot be made due toidiosyncrasies in the presentation. In these cases a diagnosis ofindeterminate colitis may be made. Other forms of IBD include, but arenot limited to, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behçet's disease and indeterminate colitis.

As used herein, the term “chronic active ulcerative colitis” refers topatients with ulcerative colitis, typically with an active disease ofgradual onset, with almost constant diarrhea mixed with blood.

As used herein, the term “colectomy” refers to surgical resection of anyextent of the large intestine (colon). Herein, colectomy includes, butis not limited to, right hemicolectomy, left hemicolectomy, extendedhemicolectomy, transverse colectomy, sigmoidectomy, proctosigmoidectomy,Hartmann operation, “double-barrel” or Mikulicz colostomy, totalcolectomy (also known as Lane's Operation), total procto-colectomy andsubtotal colectomy.

As used herein, the phrase “elective for colectomy” refers to a subjectwho may choose to undergo the procedure of non-emergency colectomy basedon physician and surgeon assessment. Subjects elective for colectomy maybe, but are not limited to, subjects refractory to available therapy orintolerant of available therapy. This differs from emergency colectomy,which is an acute intervention for subjects with acute illnesses orinjuries and who require immediate medical attention. The phrase alsoincludes subjects that are elected for colectomy.

References describing immunostimulatory activity of polynucleotidesinclude, but are not limited to, Krug et al. (2001); Bauer et al.(2001); Klinman et al. (1999); Jahn-Schmid et al. (1999) and Tighe etal. (2000).

Further references describing immunostimulatory sequences include:Tokunaga et al. (1992), Yamamoto (1992), EP468520, WO9602555, WO9728259,WO9816247, WO2007004977, WO2007004979, U.S. Pat. No. 6,339,068, U.S.Pat. No. 6,406,705, U.S. Pat. No. 6,426,334 and U.S. Pat. No. 6,426,336.

The term “immunomodulatory response” describes the change of an immuneresponse when challenged with an immunomodulatory oligonucleotide. Thischange is often measurable through the release of certain cytokines suchas interferons as well as other physiological parameters such asproliferation. The response can equally be one that serves to stimulatethe immune system as well as to repress the immune system depending onthe cytokines induced by the immunomodulatory oligonucleotide inquestion.

For purposes of the invention, the term “immunomodulatoryoligonucleotide” refers to an oligonucleotide as described below thatinduces an immune response either stimulating the immune system orrepressing the immune system or both in an organism when administered toa vertebrate, such as a mammal. As used herein, the term “mammal”includes, without limitation rats, mice, cats, dogs, horses, cattle,cows, pigs, rabbits, non-human primates, and humans.

As used herein, the term “subject” typically refers to humansubject/patient. Subjects may, however, be other vertebrate animals,such as mammals.

For purposes of the invention, the term “oligonucleotide” refers to apolynucleoside formed from a plurality of linked individual nucleosideunits. Such oligonucleotides can be obtained from existing nucleic acidsources, including genomic DNA or cDNA, plasmids, vectors, or bacterialDNA, but are preferably produced by synthetic methods. The nucleosideresidues can be coupled to each other by any of the numerous knowninternucleoside linkages. Such internucleoside linkages include, withoutlimitation, the natural internucleoside phosphodiester bond or indeedmodified internucleosides such as, but not limited to, phosphorothioate,phosphorodithioate, alkylphosphonate, alkylphosphonothioate,phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy,acetamidate, carbamate, morpholino, borano, thioether, bridgedphosphoramidate, bridged methylene phosphonate, bridgedphosphorothioate, and sulfone internucleoside linkages. The term“oligonucleotide” also encompasses polynucleosides having one or morestereospecific internucleoside linkages (e. g., (Rp)- or(Sp)-phosphorothioate, alkylphosphonate, or phosphotriester linkages).As used herein, the terms “oligonucleotide” and “dinucleotide” areexpressly intended to include polynucleosides and dinucleosides havingany such internucleoside linkage, whether or not the linkage comprises aphosphate group. In certain preferred embodiments, these internucleosidelinkages may be phosphodiester, phosphorothioate, or phosphorodithioatelinkages, or combinations thereof.

The term “oligonucleotide” also encompasses polynucleosides havingadditional substituents including, without limitation, protein groups,lipophilic groups, intercalating agents, diamines, folic acid,cholesterol and adamantane. The term “oligonucleotide” also encompassesany other nucleobase containing polymer, including, without limitation,peptide nucleic acids (PNA), peptide nucleic acids with phosphate groups(PHONA), locked nucleic acids (LNA), morpholino-backboneoligonucleotides, and oligonucleotides having backbone sections withalkyl linkers or amino linkers. The alkyl linker may be branched orunbranched, substituted or unsubstituted, and chirally pure or a racemicmixture.

The oligonucleotides of the invention can include naturally occurringnucleosides, modified nucleosides, or mixtures thereof. As used herein,the term “modified nucleoside” is a nucleoside that includes a modifiedheterocyclic base, a modified sugar moiety, or a combination thereof. Insome embodiments, the modified nucleoside is a non-natural pyrimidine orpurine nucleoside, as herein described. In some embodiments, themodified nucleoside is a 2′-substituted ribonucleoside, anarabinonucleoside or a 2′-deoxy-2′-substituted-arabinoside.

As used herein, the term “a hybrid oligonucleotide” is anoligonucleotide having more than one type of nucleoside.

Herein, the term “oligonucleotide” includes hybrid and chimericoligonucleotides. A “chimeric oligonucleotide” is an oligonucleotidehaving more than one type of internucleoside linkage within its sequencestructure. One preferred example of such a chimeric oligonucleotide is achimeric oligonucleotide comprising a phosphorothioate, phosphodiesteror phosphorodithioate region and non-ionic linkages such asalkylphosphonate or alkylphosphonothioate linkages (U.S. Pat. No.5,635,377 and U.S. Pat. No. 5,366,878).

Herein, the term “oligonucleotide” also includes circularized variantsand circular oligonucleotides.

Preferably, the immunomodulatory oligonucleotide comprises at least onenaturally occurring phosphodiester, or one modified phosphorothioate, orphosphorodithioate internucleoside linkage, however preferred linkagesor indeed backbone modifications including, without limitation,methylphosphonates, methylphosphonothioates, phosphotriesters,phosphothiotriesters, phosphorothioates, phosphorodithioates, triesterprodrugs, sulfones, sulfonamides, sulfamates, formacetal,N-methylhydroxylamine, carbonate, carbamate, morpholino,boranophosphonate, phosphoramidates, especially primaryamino-phosphoramidates, N3 phosphoramidates and N5 phosphoramidates, andstereospecific linkages (e. g., (Rp)- or (Sp)-phosphorothioate,alkylphosphonate, or phosphotriester linkages).

The sugar moiety of the nucleoside can be a non-naturally occurringsugar moiety. Herein, a “naturally occurring sugar moiety” is a sugarmoiety that occurs naturally as part of a nucleic acid, e. g., riboseand 2′-deoxyribose, and a “non-naturally occurring sugar moiety” is anysugar that does not occur naturally as part of a nucleic acid, but whichcan be used in the backbone for an oligonucleotide, for example but notlimited to hexose. Arabinose and arabinose derivatives are examples ofpreferred sugar moieties.

Modified or substituted oligonucleotides are often preferred over nativeforms because of desirable properties such as, for example, enhancedcellular uptake, enhanced affinity for nucleic acid target and increasedstability in the presence of nucleases. An oligonucleotide is usuallycomprised of more than ten (10) and up to one hundred (100) or moredeoxyribonucleotides or ribonucleotides, although preferably betweenabout eight (8) and about forty (40), most preferably between abouteight (8) and about twenty (20). The exact size will depend on manyfactors, which in turn depends on the ultimate function or use of theoligonucleotide. The oligonucleotide may be generated in any manner,including chemical synthesis, DNA replication, reverse transcription, ora combination thereof.

In one aspect, the invention provides an oligonucleotide comprising thesequence 5′-X_(m)-TTCGT-Y_(n)-3′, for use in the prevention of colectomyin a subject, wherein X is A, T, C or G, Y is A, T, C or G, m=0-12,n=0-12 and wherein at least one CG dinucleotide is unmethylated.

In one embodiment of this aspect, there is provided an oligonucleotidefor use in the prevention of colectomy, wherein said oligonucleotidecomprises the sequence 5′-X_(m)-CAGTTCGTCCA-Y_(n)-3′, wherein X is A, T,C or G, Y is A, T, C or G, m=0-8, n=0-8, and wherein at least one CGdinucleotide is unmethylated.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein at leastone nucleotide has a phosphate backbone modification.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein at leastone nucleotide has a phosphorothioate or a phosphorodithioatemodification.

The phosphorothioate linkages can be illustrated with asterisks (*) inthe sequence:

5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), wherein the CGdinucleotide is unmethylated.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein saidoligonucleotide has the sequence 5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′(SEQ IDNO:1), and wherein the CG dinucleotide is unmethylated.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein saidoligonucleotide has the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ IDNO:2), and wherein the CG dinucleotide is unmethylated.

The present invention also provides oligonucleotides for use in methodsof the invention, having the sequence: 5′-Xm-CG-Y_(n)-3′, wherein X isA, T, C or G, Y is A, T, C or G; m=1-100, n=1-100 and wherein at leastone CG dinucleotide is unmethylated. Further, there is providedoligonucleotides for use in methods of the invention, having thesequence: 5′-Xm-CG-Y_(n)-3′, wherein X is A, T, C or G, Y is A, T, C orG, m is 1-100 and n is 1-100; m is 1-80 and n is 1-80; m is 1-60 and nis 1-60; m is 1-40 and n is 1-40; m is 1-20 and n is 1-20; m is 1-12 andn is 1-12; m is 1-10 and n is 1-10; m is 1-8 and n is 1-8; m is 1-6 andn is 1-6, and wherein at least one CG dinucleotide is unmethylated.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy in a subject,wherein said subject is suffering from an IBD. Said IBD may be chronicactive ulcerative colitis. Further, said IBD may be Crohn's disease.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein saidsubject is refractory or responds insufficiently or is intolerant toanti-inflammatory therapy.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein saidoligonucleotide is administered as an add-on to a current therapy.

As used herein, the term “add-on” refers to administering of saidoligonucleotides in addition to a current therapy or drug regime,without discontinuing the current therapy or drug regime.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein saidoligonucleotide is administered intracolonically. Intracolonicaladministration may be topical, for example performed during colonoscopywith the aid of a spraying catheter, or other suitable medicalequipment, inserted though the colonoscopies biopsy channel. The saidoligonucleotide may be delivered to the upper portion of the descendingcolon or to the transverse region of the colon; however other regionsare also possible when suited. Topical administration to other parts ofthe gastrointestinal tract is also possible. Yet in another embodimentof this aspect, the said oligonucleotides can be administered by anyappropriate administration route, such as, but not limited to,inhalation, intranasal, parenteral, oral, intradermal, subcutaneous,vaginal and rectal administration. Further, in certain embodiments,systemic administration of said oligonucleotide may be used.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein saidsubject is elective for colectomy.

In another embodiment of this aspect, there is provided anoligonucleotide for use in the prevention of colectomy, wherein saidcolectomy is prevented or delayed, typically for at least 5 months. Forexample, colectomy may be prevented for 9, 12, 13, 17, 18, 19, 23, 24,27 or 31 months or longer. Preferably colectomy is preventedindefinitely.

In some embodiments said oligonucleotide is administered in combinationwith other drugs, for example immunomodulatory drugs or anti-TNF therapydrugs or other suitable drugs. Examples of such drugs include, but arenot limited to, glucocorticosteroids, cyclosporine, Infliximab,Adallilumab, natural IFN-β, Decortin, S-Ompeprazol, 5-Asa, Azathioprin,Prednisolon and equivalents thereof.

In some embodiments, said oligonucleotide is administered in combinationwith one or many steroid drugs, for example corticosteroids andglucocorticosteroids.

For purposes of the invention, the terms “in combination with” and“add-on” mean in the course of treating the same disease in the samepatient, and include administering the immunomodulatory oligonucleotidein any order, including simultaneous administration, as well astemporally spaced order of up to several months apart. Such combinationtherapy may also include one or repetitive administration of singledoses or exposures of the immunomodulatory oligonucleotide. For example,the immunomodulatory oligonucleotide may be given to a subject,typically a patient, that has started or is undergoing steroid therapyfor an IBD, for example UC or Crohn's disease.

In some embodiments, said oligonucleotides may be administered incombination with an increased dose of one or more immunomodulatory drugsin order for the subject to enter into remission by any means (or asjudged by any relevant clinical manifestation), such as CAI score ≦4. Inanother embodiment, an additional dose(s) of said oligonucleotide may begiven to the subject in an instance of relapse, as determined forexample by a deterioration of the disease to a CAI score of ≧4 or otherrelevant clinical manifestation.

The embodiments of the aspect of the use of said oligonucleotide in theprevention of colectomy mentioned above, are also valid for the methodaspects of the present invention listed below.

In another aspect of the invention, there is provided a method forpreventing colectomy, comprising administering an effective exposure ofan oligonucleotide comprising the sequence 5′-X_(m)-TTCGT-Y_(n)-3′, to asubject in need thereof, wherein X is A, T, C or G, Y is A, T, C or G,m=0-12, n=0-12, and wherein at least one CG dinucleotide isunmethylated.

The phrase “an effective amount” as used herein relates to an amountsufficient to prevent or reduce the need of colectomy in a subject. Forexample an amount sufficient to prevent or reduce the need of colectomyfor at least 2-3 months, more preferably for at least 5 or 6 months, andeven more preferable for longer time. Most preferably colectomy isprevented indefinitely and complete clinical remission is maintained, asdefined by a CAI score of 0 or 1, with a concomitant endoscopic score of0-3, or as judged by other relevant clinical manifestations.

In one embodiment of this aspect, said oligonucleotide comprises thesequence 5′-X_(m)-CAGTTCGTCCA-Y_(n)-3′, wherein X is A, T, C or G, Y isA, T, C or G, m=0-8, n=0-8, and wherein at least one CG dinucleotide isunmethylated.

In another embodiment of this aspect, said oligonucleotide has at leastone nucleotide which has a phosphate backbone modification.

In another embodiment of this aspect, said oligonucleotide has at leastone nucleotide which has a phosphorothioate or a phosphorodithioatemodification.

In another embodiment of this aspect, said oligonucleotide has thesequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), and wherein the CGdinucleotide is unmethylated.

In another embodiment of this aspect, said oligonucleotide has thesequence 5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), and wherein theCG dinucleotide is unmethylated.

In another embodiment of this aspect, said subject is suffering from anIBD. Said IBD may be chronic active ulcerative colitis. Further, saidIBD may be Crohn's disease.

In another embodiment of this aspect, said subject is refractory orresponds insufficiently or is intolerant to anti-inflammatory therapy.

In another embodiment of this aspect, said oligonucleotide isadministered as an add-on to a current therapy.

In another embodiment of this aspect, said oligonucleotide isadministered topically, such as topically to the mucous membrane.

In another embodiment of this aspect, said oligonucleotide isadministered intracolonically. Intracolonical administration may betopical, for example performed during colonoscopy with the aid of aspraying catheter, or other suitable medical equipment, inserted thoughthe colonoscopies biopsy channel. The said oligonucleotide may bedelivered to the upper portion of the descending colon or to thetransverse region of the colon; however other regions are also possiblewhen suited. Topical administration to other parts of thegastrointestinal tract is also possible. Yet in another embodiment ofthis aspect, the said oligonucleotides can be administered by anyappropriate administration route, such as, but not limited to,inhalation, intranasal, parenteral, oral, intradermal, subcutaneous,vaginal and rectal administration. In certain embodiments of theinventive method, systemic administration of said oligonucleotide may beused.

In another embodiment of this aspect, said subject is elective forcolectomy.

In another embodiment of this aspect, the said colectomy is preventedfor at least 5 months. For example, colectomy may be prevented for 9,12, 13, 17, 18, 19, 23, 24, 27 or 31 months or longer. Preferablycolectomy is prevented indefinitely.

In another aspect, the invention provides a pharmaceutical compositioncomprising an oligonucleotide having the sequence5′-X_(m)-TTCGT-Y_(n)-3′, wherein X is A, T, C or G, Y is A, T, C or G,m=0-12, n=0-12, and wherein at least one CG dinucleotide isunmethylated, together with one or more pharmaceutically acceptableexcipient(s) and/or carrier(s), for use in the prevention of colectomy.

In one embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidoligonucleotide is having the sequence 5′-X_(m)-CAGTTCGTCCA-Y_(n)-3′,wherein X is A, T, C or G, Y is A, T, C or G, m=0-8, n=0-8, and whereinat least one CG dinucleotide is unmethylated.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidoligonucleotide has at least one nucleotide which has a phosphatebackbone modification.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidoligonucleotide has at least one nucleotide which has a phosphorothioateor a phosphorodithioate modification.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidoligonucleotide has the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ IDNO:2), and wherein the CG dinucleotide is unmethylated.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidoligonucleotide has the sequence 5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ IDNO:1), and wherein the CG dinucleotide is unmethylated.

As used herein, the term “carrier” encompasses any excipient, diluent,filler, salt, buffer, water, stabilizer, solubilizer, lipid, or othermaterial well known in the art for use in pharmaceutical formulations.It will be understood that the characteristics of the carrier,excipient, or diluent will depend on the route of administration for aparticular application.

As used herein, the term “pharmaceutically acceptable” refers to amaterial that does not interfere with the effectiveness of theimmunomodulatory oligonucleotide and is compatible with a biologicalsystem such as a cell, cell culture, tissue, or organism. Preferably,the biological system is a living organism, such as a vertebrate.

In one embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein the amountof said oligonucleotide is present in the range from about 0.3 mg toabout 100 mg.

In one embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein the amountof said oligonucleotide is present in the range from about 25 mg toabout 60 mg.

In one embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein the amountof said oligonucleotide present within the said composition is about 30mg.

The concentration of an immunomodulatory oligonucleotide in apharmaceutically acceptable mixture will vary depending on severalfactors, including the dosage of the compound to be administered, thepharmacokinetic characteristics of the compound(s) employed, the age,sex and condition of the patient, as well as the route ofadministration. Effective amounts of immunomodulatory oligonucleotidesfor preventing or reducing the need for colectomy in a subject wouldbroadly range between about 0.3 mg to about 100 mg, preferably about3-30 mg, and most preferably about 30 mg.

As used herein, the term “exposure” refers to an administration of anoligonucleotide, wherein a constant drug dose elicits increasing effectsand does not refer to cumulative drug effect.

In one embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidcomposition is repetitively administered as a single exposure.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidcomposition is repetitively administered as a single exposure on two ormore separate occasions.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidcomposition is repetitively administered as a single exposure on two ormore separate occasions 4 to 70 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidcomposition is repetitively administered as a single exposure on twoseparate occasions 4 to 8 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein saidcomposition is repetitively administered as a single exposure on threeseparate occasions 4 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein the saidcomposition is repetitively administered as a single exposure on twoseparate occasions 4 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein the saidcomposition is administered topically, such as topically to the mucosalmembrane.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the prevention of colectomy, wherein the saidcomposition is administered intracolonically.

In another aspect, the invention provides a pharmaceutical compositioncomprising an oligonucleotide having the sequence5′-X_(m)-TTCGT-Y_(n)-3′, wherein X is A, T, C or G, Y is A, T, C or G,m=0-12, n=0-12, and wherein at least one CG dinucleotide isunmethylated, together with one or more pharmaceutically acceptableexcipient(s) and/or carrier(s), for use in the treatment of chronicactive ulcerative colitis, wherein the composition is repetitivelyadministered as a single exposure.

In one embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide has the sequence5′-X_(m)-CAGTTCGTCCA-Y_(n)-3′, wherein X is A, T, C or G, Y is A, T, Cor G, m=0-8, n=0-8, and wherein at least one CG dinucleotide isunmethylated.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide has at least one nucleotide whichhas a phosphate backbone modification.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide has at least one nucleotide whichhas a phosphorothioate or a phosphorodithioate modification.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide has the sequence5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), and wherein the CG dinucleotideis unmethylated.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide has the sequence5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), and wherein the CGdinucleotide is unmethylated.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide is administered in amount of fromabout 0.3 mg to about 100 mg.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide is administered in amount of fromabout 25 mg to about 60 mg.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said oligonucleotide is administered in amount of about30 mg. In another embodiment of this aspect, there is provided apharmaceutical composition for use in the treatment of chronic activeulcerative colitis, wherein said composition is repetitivelyadministered as a single exposure.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said composition is repetitively administered as asingle exposure on two or more separate occasions 4 to 70 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said composition is repetitively administered as asingle exposure on two separate occasions 4 to 8 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said composition is repetitively administered as asingle exposure on two separate occasions 4 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein said composition is repetitively administered as asingle exposure on three separate occasions 4 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidoligonucleotide has at least one nucleotide which has a phosphatebackbone modification.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidoligonucleotide has at least one nucleotide which has a phosphorothioateor a phosphorodithioate modification.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidoligonucleotide has the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ IDNO:2), and wherein the CG dinucleotide is unmethylated.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidoligonucleotide has the sequence 5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ IDNO:1), and wherein the CG dinucleotide is unmethylated.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidoligonucleotide is administered in amount of from about 0.3 mg to about100 mg.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidoligonucleotide is administered in amount of from about 25 mg to about60 mg.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidoligonucleotide is administered in amount of about 30 mg.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidcomposition is repetitively administered as a single exposure.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidcomposition is repetitively administered as a single exposure on two ormore separate occasions 4 to 70 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidcomposition is repetitively administered as a single exposure on twoseparate occasions 4 to 8 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidcomposition is repetitively administered as a single exposure on twoseparate occasions 4 weeks apart.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein saidcomposition is repetitively administered as a single exposure on threeseparate occasions 4 weeks apart.

The person skilled in the art realizes that the present invention by nomeans is limited to the preferred embodiments described above. On thecontrary, many modifications and variations are possible within thescope of the appended claims.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein the said composition is administered topically, such astopically to the mucosal membrane.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein thesaid composition is administered topically, such as topically to themucosal membrane.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of chronic active ulcerativecolitis, wherein the said composition is administered intracolonically.

In another embodiment of this aspect, there is provided a pharmaceuticalcomposition for use in the treatment of Crohn's disease, wherein thesaid composition is administered intracolonically.

In another aspect of the invention, there is provided an oligonucleotidecomprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), whereinat least one CG dinucleotide is unmethylated, for use in the treatmentof an inflammatory bowel disease in a subject that is refractory orresponds insufficiently or is intolerant to anti-inflammatory therapy,wherein said oligonucleotide is repetitively administered as a singleexposure.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein at least one nucleotide in saidoligonucleotide has a backbone modification. Typically, said backbonemodification is a phosphate backbone modification, represented by aphosphorothioate or a phosphorodithioate modification. Further, saidphosphate backbone modification is preferably located in the 5′- and/orthe 3′-end of said oligonucleotide.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide has the sequence5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), wherein the CGdinucleotide is unmethylated.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said inflammatory bowel disease isulcerative colitis.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said inflammatory bowel disease ischronic active ulcerative colitis

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said inflammatory bowel disease isCrohn's disease.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide is repetitivelyadministered as a single exposure on two or more separate occasions 4 ormore weeks apart.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide is repetitivelyadministered as a single exposure on separate occasions 4 to 8 weeksapart.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide is repetitivelyadministered as a single exposure on three separate occasions 4 weeksapart.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide is repetitivelyadministered as a single exposure on two separate occasions 4 weeksapart.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein the amount of said oligonucleotide ispresent in the range from about 0.3 mg to about 100 mg, preferably inthe range from about 25 mg to about 60 mg, more preferably in an amountof about 30 mg.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide is administered asan add-on to a current therapy.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide is administeredtopically to mucosal membranes.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said oligonucleotide is administeredintracolonically.

In another embodiment of this aspect, there is provided anoligonucleotide for use, wherein said subject is elective for colectomy.Typically, said colectomy is prevented or delayed.

In another aspect of the invention, there is provided a pharmaceuticalcomposition comprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ IDNO:2) and wherein at least one CG dinucleotide is unmethylated, togetherwith one or more pharmaceutically acceptable excipient(s) and/orcarrier(s), for use in the treatment of an inflammatory bowel disease ina subject that is refractory or responds insufficiently or is intolerantto anti-inflammatory therapy, wherein said composition is repetitivelyadministered as a single exposure.

In one embodiment of this aspect, there is provided a composition foruse, wherein at least one nucleotide in said oligonucleotide has abackbone modification. Typically, said backbone modification is aphosphate backbone modification, represented by a phosphorothioate or aphosphorodithioate modification. Further, said phosphate backbonemodification is preferably located in the 5′- and/or the 3′-end of saidoligonucleotide.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said oligonucleotide has the sequence5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), wherein the CGdinucleotide is unmethylated.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said inflammatory bowel disease is ulcerative colitis.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said inflammatory bowel disease is chronic activeulcerative colitis.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said inflammatory bowel disease is Crohn's disease.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said composition is repetitively administered as asingle exposure on two or more separate occasions 4 or more weeks apart.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said composition is repetitively administered as asingle exposure on separate occasions 4 to 8 weeks apart.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said composition is repetitively administered as asingle exposure on three separate occasions 4 weeks apart.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said composition is repetitively administered as asingle exposure on two separate occasions 4 weeks apart.

In another embodiment of this aspect, there is provided a compositionfor use, wherein the amount of said oligonucleotide is present in therange from about 0.3 mg to about 100 mg, preferably from about 25 mg toabout 60 mg, more preferably about 30 mg.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said composition is administered as an add-on to acurrent therapy.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said composition is administered topically to mucosalmembranes.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said composition is administered intracolonically.

In another embodiment of this aspect, there is provided a compositionfor use, wherein said subject is elective for colectomy. Typically, saidcolectomy is prevented or delayed.

In another aspect of the invention, there is provided a method oftreating an inflammatory bowel disease in a subject that is refractoryor responds insufficiently or is intolerant to anti-inflammatorytherapy, comprising administering to a patient in need thereof, aneffective exposure of an oligonucleotide comprising the sequence5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2) and wherein at least one CGdinucleotide is unmethylated, wherein said oligonucleotide isrepetitively administered as a single exposure.

In one embodiment of this aspect, at least one nucleotide in saidoligonucleotide has a backbone modification. Typically, said backbonemodification is a phosphate backbone modification, represented by aphosphorothioate or a phosphorodithioate modification. Further, saidphosphate backbone modification is preferably located in the 5′- and/orthe 3′-end of said oligonucleotide.

In another embodiment of this aspect, said oligonucleotide has thesequence 5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), wherein the CGdinucleotide is unmethylated.

In another embodiment of this aspect, said inflammatory bowel disease isulcerative colitis.

In another embodiment of this aspect, said inflammatory bowel disease ischronic active ulcerative colitis.

In another embodiment of this aspect, said inflammatory bowel disease isCrohn's disease.

In another embodiment of this aspect, said oligonucleotide isrepetitively administered as a single exposure on two or more separateoccasions 4 or more weeks apart.

In another embodiment of this aspect, said oligonucleotide isrepetitively administered as a single exposure on separate occasions 4to 8 weeks apart.

In another embodiment of this aspect, said oligonucleotide isrepetitively administered as a single exposure on three separateoccasions 4 weeks apart.

In another embodiment of this aspect, said oligonucleotide isrepetitively administered as a single exposure on two separate occasions4 weeks apart.

In another embodiment of this aspect, the amount of said oligonucleotideis in the range from about 0.3 mg to about 100 mg, preferably, fromabout 25 mg to about 60 mg more preferably about 30 mg.

In another embodiment of this aspect, said composition is administeredas an add-on to a current therapy.

In another embodiment of this aspect, said oligonucleotide isadministered topically to mucosal membranes.

In another embodiment of this aspect, said oligonucleotide isadministered intracolonically.

In another embodiment of this aspect, said subject is elective forcolectomy. Typically, said colectomy is prevented or delayed.

EXAMPLES

Patient Selection

Over the course of two and a half years 14 chronic active UCout-patients were treated with DIMS0150 (SEQ ID NO:1) as add-on to theircurrent therapies with 3 subjects receiving 3 doses of DIMS0150 (SEQ IDNO:1) with 4 weeks between exposure occasions. A diagnosis of UC wasestablished in all patients based on clinical, endoscopic andhistological features. All patients were judged as being therapyfailures with a documented history of not responding adequately toeffective dosing regimens of available therapies including high dose i.vglucocorticoids and were considered for elective colectomy based on thetreating physician and surgeon's assessment. Base line characteristicsare given in Table 1. Subjects who were deemed likely to require promptclinical intervention or cases of expected colectomy were notconsidered.

Safety and Efficacy

The suitability of DIMS0150 (SEQ ID NO:1) was evaluated as a potentialrescue therapy to prevent colectomy, on a midterm basis of 6 months, ifcolectomy was elected as the preferred therapy option. Other objectivesaddressed response (a decrease in CAI score by ≧5 units from baseline)or remission (CAI score of ≦4 points) and the prevention of colectomy ona long term basis of more than 6 months.

TABLE 1 Demographic Overview of the Patients Disease Current Patient AgeSex Duration Disease Extent Therapy History Medication p1 30 female >3years Pancolitis Intolerant to GCS; Azathioprin refractory to 50 mg/day,Infliximab, 5-Asa 4 g/day Adalilumab; natural IFN-β p2 22 male 6 yearsPancolitis Refractory to GCS, Decortin Infliximab, 20 mg/day, S-Adalilumab, natural Ompeprazol IFN-β 20 mg/day p3 44 male 20 yearsColitis of rest Refractory to GCS Decortin colon after and Infliximab 40mg/day, 5-Asa hemicolectomy 4 g/day (ano-50 cm) p4 68 male 1 yearUlcerative colitis Refractory to GCS Decortin (ano-80 cm) 30 mg/day,5-Asa 4.5 g/day p5 45 male 4 years Pancolitis Refractory to GCS,Decortin Infliximab, natural 35 mg/day, 5-Asa IFN-β 3 g/day p6 54 female4 years Proctitis Refractory to GCS 5-Asa (ano-15 cm) and Infliximab 4g/day p7 74 female >3 years Proctitis Refractory to GCS 5-Asa (ano-20cm) 1.5 g/day p8 46 female 29 years Ulcerative colitis Refractory to GCSDecortin (ano-80 cm) 10 mg/day, Azathioprin 125 mg/day p9 60 male >3years Ulcerative colitis Intolerant to GCS; 5-Asa (ano-60 cm) refractoryto 2 g/day Infliximab p10 27 male 4 years Ulcerative colitis Refractoryto GCS Decortin (ano-60 cm) and Infliximab 20 mg/day, Azathioprin 150mg/day, 5-Asa 4 g/day p11 46 female 25 years ProctosigmoiditisRefractory to GCS Decortin (ano-35 cm) 10 mg/day, Azathioprin 100 mg/dayp12* 50 male 5 years Pancolitis Refractory to GCS, Decortin Infliximab,natural 25 mg/day IFN-β p13* 36 female 7 years Ulcerative colitisRefractory to GCS Decortin (ano-70 cm) and intolerant to 40 mg/dayimmune suppressants p14* 50 female 2 years Ulcerative colitis Refractoryto GCS Decortin (ano-110 cm) 40 mg/day, Azathioprin 100 mg/day *Subjectsreceived three exposures of DIMS0150 (SEQ ID NO: 1). Data compiled fromAugust 2008 to March 2011.

Endoscopy was assessed according to the Rachmilewitz composed activityindex (Rachmilewitz, 1989) scale (0-12) where endoscopic response wasdefined as a decrease of ≧4 units from baseline and complete endoscopicremission is represented by 0-3. Histological assessments were made inaccordance to the Geboes et al., (2000) scale (0-5) where a response wasdefined as a decrease of ≧3 units from baseline and complete resolutionis indicated by a score of zero. Complete remission was defined as a CAIscore of 0 or 1, with a concomitant endoscopic score of 0-3. Clinicalassessment of the efficacy parameters were made at weeks 1, 4 and 12.Those patients that received additional exposure(s) of DIMS1050 (SEQ IDNO:1) due to a relapse of symptoms were likewise evaluated at weeks 1, 4and 12. For all visit occasions, adverse events were recorded.

Therapy

Eleven patients received a single intracolonical administration of 30 mgof DIMS0150 (SEQ ID NO:1) diluted in 50 mL of sterile water in additionto their current therapies. Application of drug was performed duringcolonoscopy with the aid of a spraying catheter inserted through thecolonoscopies biopsy channel and delivered approximately to the upperportion of the descending colon or to the transverse region. Ininstances of a relapse (as determined by a deterioration of the diseaseof ≧4 CAI units) an additional exposure(s) of DIMS0150 (SEQ ID NO:1) wasoffered and the patient subsequently followed.

Three patients received 3 doses of DIMS0150 (SEQ ID NO:1) at 4 weeksintervals. Table 2 outlines patient's base-line characteristics andclinical response parameters, at weeks 1, 4 and 12 and time ofadditional exposure(s) in those subjects who experienced a relapse.

TABLE 2 Disease Activity Overview of Patients Time point(s) of DiseaseActivity at Disease Activity at Disease Activity at additional Dosing 4wks 12 wks DIMS0150 Patient CAI Endo Histo CAI Endo Histo CAI Endo Histoexposure Follow-up p1 15 10 5 8 8 4 3 2 2  4 mths 31 mths p2 10 10 5 0 55 4 4 5 6 and 12 Colectomized mths after 17 mths p3 14 9 5 4 3 2 5 5 35, 10, 20, 23 27 mths and 26 mths p4 13 10 3 6 3 3 1 0 1 11 mths 24 mthsp5 12 10 5 4 1 3 2 1 2 16, 17 and 23 mths 18 mths* p6 14 10 5 8 7 5Colectomized after 3 mths p7 12 9 5 5 5 4 2 5 4 19 mths p8 11 9 5 6 5 14 4 0 18 mths p9 9 7 3 7 5 3 4 2 1 17 mths p10 10 9 5 6 5 4 0 2 1 15mths p11 9 5 3 6 5 3 6 5 3 13 mths p12* 9 8 5 1 5 3 0 0 0 4 and 8 12mths weeks p13* 13 9 5 4 7 3 2 3 1 4 and 8  9 mths weeks p14* 14 10 4 05 5 2 2 2 4 and 8  5 mths weeks *Subjects received 3 exposuresof SEQ IDNO: 1 with 4 weeks between each exposure. Data compiled from August 2008to March 2011Single Exposure

After therapy with DIMS0150 (SEQ ID NO:1), 73% (8/11) of patients had aclinical response and 27% (3/11) were in remission by week 4. At week12, clinical response and remission rates were 91% (10/11) and 73%(8/11) respectively, with 2 cases of complete clinical remission. FIG. 1illustrates the median CAI score observed in those subjects receiving asingle or multiple exposures across the 12 week period.

Endoscopic evaluation at week 4, showed that 64% (7/11) of subjects hada endoscopic response with 27% (3/11) in endoscopic remission. By week12, an endoscopic response was seen in 73% (8/11) of patients with 45%(5/11) in remission. FIG. 2 illustrates the median endoscopic scoresacross the 12 week period. Of those subjects receiving a single ormultiple exposures to SEQ ID NO:1. For histological evaluation, threebiopsy specimens representing three colonic regions (ascending,transverse and descending, respectively) were assessed and the scoresare given in Table 2. At week four 18% (2/11) of patients had ahistological response and by week 12 this value had increased to 36%(4/11) with 9% (1/11) in histological remission (see Table 3). FIG. 3illustrates the median histological scores between single and multipleexposures groups across the 12 week period. Five patients (p1-p5) weregiven additional exposures of DIMS0150 (SEQ ID NO:1) due to a relapse ofsymptoms at the times indicated (Table 2). All subjects had animprovement in their CAI scores following further therapy with DIMS0150.As a consequence to responding to DIMS0150 all, with the exception oftwo patients, had so far avoided the need for colectomy (FIG. 4), withthe longest period being currently around 40 months (as of end of 2011).Despite initially responding to DIMS0150 (SEQ ID NO:1), patients (p2 andp6) decided to undergo colectomy some 17 and 3 months after firsttherapy respectively.

Multiple Exposures

Three patients (p12-14)) were administered three exposures of 30 mgDIMS0150 (SEQ ID NO:1) as add-on to current therapies with 4 weekintervals between each exposure. The clinical response parameters areprovided in Table 3 and interestingly there is a clear improvement inthe efficacy parameters at 12 weeks when compared to those valuesachieved with just a single exposure. This improvement is also evidentfrom FIGS. 2, 3 and 4. Considered collectively, the data seen betweenthe two groups of subjects suggests that multiple exposures with a timeframe of 4 weeks between exposures resulted in an improved clinicaloutcome.

TABLE 3 Rates of disease activity measurements Clinical responseClinical remission 4 wks 12 wks 4 wks 12 wks Single Exposure  73%  91% 27%  73% (n = 11)  (8/11) (10/11)  (3/11)  (8/11) Multiple Exposures100% 100% 100% 100% (n = 3) (3/3) (3/3) (3/3) (3/3) Endoscopic responseEndoscopic remission 4 wks 12 wks 4 wks 12 wks Single Exposure 64%  73%27%  45% (n = 11)  (7/11)  (8/11)  (3/11)  (5/11) Multiple Exposures 33%100%  0% 100% (n = 3) (1/3) (3/3) (0/3) (3/3) Histological responseHistological remission 4 wks 12 wks 4 wks 12 wks Single Exposure 18% 36%0%  9% (n = 11)  (2/11)  (4/11)  (0/11)  (1/11) Multiple Exposures  0%67% 0% 33% (n = 3) (0/3) (2/3) (0/3) (1/3)

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The invention claimed is:
 1. A method of treating chronic activeulcerative colitis in a subject that is refractory or respondsinsufficiently or is intolerant to anti-inflammatory therapy, comprisingadministering to the subject an effective exposure of an oligonucleotidecomprising the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), whereinat least one CG dinucleotide is unmethylated, and wherein saidoligonucleotide is not administered in combination with corticosteroidor glucocorticosteroid.
 2. The method of claim 1, wherein at least onenucleotide in said oligonucleotide has a backbone modification.
 3. Themethod of claim 2, wherein said backbone modification is a phosphatebackbone modification represented by a phosphorothioate or aphosphorodithioate modification.
 4. The method of claim 2, wherein saidbackbone modification is located in the 5′- and/or the 3′-end of saidoligonucleotide.
 5. The method of claim 1, wherein said oligonucleotidehas the sequence 5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), whereinthe CG dinucleotide is unmethylated.
 6. The method of claim 1, whereinindividual doses of said oligonucleotide are repetitively administeredas a single exposure.
 7. The method of claim 1, wherein two or moredoses of said oligonucleotide are administered on two or more separateoccasions 4 to 70 weeks apart.
 8. The method of claim 1, wherein theamount of said oligonucleotide administered is in the range from about0.3 mg to about 100 mg.
 9. The method of claim 1, wherein the amount ofsaid oligonucleotide administered is in the range from about 25 mg toabout 60 mg.
 10. The method of claim 1, wherein the amount of saidoligonucleotide administered is about 30 mg.
 11. The method of claim 1,wherein said oligonucleotide is administered in combination with one ormore other drugs.
 12. The method of claim 1, wherein saidoligonucleotide is administered in combination with one or moreimmunomodulatory drugs or anti-TNF therapy drugs.
 13. The method ofclaim 1, wherein said oligonucleotide is administered in combinationwith one or more of cylclosporine, Infliximab, Adallilumab, naturalIFN-β, S-Ompeprazol, 5-Asa, or Azathioprin.
 14. The method of claim 1,wherein said oligonucleotide is administered topically to mucousalmembranes.
 15. The method of claim 1, wherein said oligonucleotide isadministered intracolonically.
 16. The method of claim 1, wherein saidsubject is elective for colectomy.
 17. The method of claim 1, whereinthe oligonucleotide is administered in the form of a pharmaceuticalcomposition comprising the oligonucleotide together with one or morepharmaceutically acceptable excipient(s) and/or carrier(s).
 18. Themethod of claim 17, wherein said composition comprises saidoligonucleotide and water.